Process of treating pregnene compounds



PatenteclFeb. 22, 194a f e I 2 452 133 Merck & 00., Inc, Railway, N. 1.,a corporation of New Jersey No Drawing. Original application .iuly 14,1945,

Serial No. 605,194. Divided and this application February 2.8, 1946,Serial No. 649,768

4 Claim. (Cl. 260397.3)

UNITED STATES PATIENT OFFICE -l 2 This invention is concerned generallywith shown by writing the'C-i'I substituenflhydroxyl) novel chemicalcompounds of the cycloto the right of the C 17 carbon side chain, thinpentanodimethylpolyhydrophenanthrene series OH'OH and v to. processes ofpreparing same; more particularly it relates to novel compounds useful aas intermediates in the synthesis of the adrenal k cortical hormone A-3,ll,20-triketo-17(p), 21- I, dihydroxy pre'gnene. This application isa diviin the latter case above the side chain, thus sional of copendingapplication Serial No. v on 605,194 filed July 14, 1945, now abandoned.I

This hormone is known to occur naturally in V the adrenal cortex; it hasthe structural formula. 3. The stermemical relationship of ma A and B isindicated in the formulae by a solid m =0 line representing the valencebond in the cis g, H J: on configuration.

c i The starting material employed intheprocesses =c{ according to thisinvention, A -'-3,11-diketo- C D 17,20,21-trihydroxypregnene can beprepared by 6, 8K :3 15 H si n iph; llulrdrolysis using conventionalmethods. of

a r A diketo l'l-hydroxy-20,21-diacyloxyn,c( to(c pregnene, which may beobtained as described A in copending application Serial No. 649,766,flied 7 H February 23, 1946. 0= 3 6 I In accordance with this inventionA -B 11- i diketo-l7-20,2l-trihydroxypregnene is partially K HI acylatedwith an acid anhydride to yieldA"-3,11- Standard numbering ofC-poaltions diketo 17-20 dihydr y 21 y ypre nene having the structuralformula:

This formula, for purposes 0! convenience, is

hereinafter reproduced below in the abbreviated form: cmo x cm HOE Bbeing acyl. Among the acid anhydrides which are useful for this purposeare those derived from propionic, butyric, valeric, caproic or capricacid.

In the following description of the invention, preferably from a loweraliphatic acid, 1. e. one the stereochemical relationships ofsubstitutes are having 6 carbon atoms or less. If preferred, theindicated by the following conventions: corresponding acid may besubstituted in whole 1. A substituent at the C-3 position which is orpart for theanhydride used,but theanhydrides trans to the C-10 methylgroup is parenthetically are preferred. In efiecting this partialacylation, designated (a). it is important not to usean amount ofacylating 2. A substituent at the 0-17 position, the agent greatly inexcess of an equimolecular stereochemical configuration of which isidentical proportion as otherwise loss of the desired monowith that ofthe naturally occurring adrenal acylated compound results because offormation hormones, is parenthetically designated (a); the of theundesired diacyl compound. Upon oxidaepimeric configuration isdesignated (a) In the tion of this compound, e.g. with chromiumstructural formulae the former configuration is trioxide, a mixture ofA"-8,l1,20-trilreto-1'l- The compounds A -3,11,20-triketo-17 (p)hydroxy-21-acyloxypregnene and A--3,11,17- triketoandrostene may beseparated from each other by the usual chromatographic methods andfractional crystallization. The compound A 3-l1,l7-triketoandrostene,also known as adrenosterone, has been found to occur naturally in theadrenal cortex.

That oxidation of a compound of thecyclopentano-dimethylpolyhydrophenanthrene series having a l'l-positionsubstituent:

cmoa

would result in a corresponding compound having a group:

cuioa kon in the same position (R is an acyl group) is particularlysurprising. Prior art attempts to accomplish this heretofore in terms ofreactions upon similar polynuclear compounds have led to splitting oil?of the side chain. According to this invention however the 1'!substituent CHsOH in a compound of thecyclopentanodimethylpolyhydro-phenanthrene series is obtained eventhough the l'l-hydroxyl group is not protected by conversion to an esterorother protective group, although the C-21 group, it will be noted, isprotected against oxidation by acylation.

In practicing the instant invention, the oxidation is carried out undermild conditions, preferably at room temperature, in a medium having a pHof 1 to 7, using a strong oxidizing agent. preferably chromium trioxide.The preferred medium is aqueous acetic acid, although if desired otherlower (6 carbon atoms or less) aliphatic monocarboxylic acids can beemployed. Acetone also has been found to be a suitable medium for thisoxidation reaction.

The following example illustrates the partial acetylation of A--3-1l-diketo-1'l (p) -20,21-trihydroxypregnene, followed by theoxidation of the resultant compound to produce A -3-11-20- triketo-l'l(p) -hydroxy-21-acetoxypregnene and A- -3,i1,17-triketoandrostene. Itwill be understood this example is for purposes of illustration and thatthe invention is not limited thereto.

Example 179.5 mg. of A -SJI-diketo-I'I (p)-20.21-trihydroxypregnene weredissolved in .5 cc. of absolute dioxane with heating. The solution wascooled to room temperature and treated with a mixture of 63.5 mg. ofpyridine and 68.5 mg. of acetic anhydride, and permitted to stand atroom temperature overnight. Water was then added. the mixtureconcentrated in vacuo and extracted with chloroform. The chloroformsolution was washed with water, concentrated to dryness, and the residuepurified by chromatography. The 21- monoacetate so obtained in aboutyield had a melting point of 172-174 C.

A solution of 165 mg. of A -3,1l-diketo-l'l (p)20-dihydroxy-2l-acetoxypregnene in 13 cc. of glacial acetic acid and 2cc. of water was cooled to 11 C. and treated with 85 mg. of chromic acidin 1.6 cc. of water. The solution was kept at 11 C. for 15 minutes, thenat 24 C. for 75 minutes. The excess chromic acid was neutralized with afew drops of dilute sodium sulfite solution and the solvent removed invacuo. The residue was extracted with chloroform, washed successivelywith dilute sodium carbonate solution and water, and concentrated todryness in vacuo. The residue was dissolved in a small volume of benzeneand chromatographed on a column containing 5 grams of neutral aluminapreviously activated at C. The elution of the chemical compound from thecolumn was carried out by the addition of 20 cc. portions of solvents,beginning with absolute ether, proceeding through ether-chloroformmixtures with an increasing proportion of chloroform, and finally withpure chloroform. Each fraction was worked up by itself. The initialfractions consisted of A -3,11,l7-triketoandrostene, having a meltingpoint of 222-224 C. [a] +281, while the latter fractions consisted of A-3,11,20-triketo-l7 (B) -hydroxy 21 acetoxypregnene, having a meltingpoint of 235- 238 c. [u] +164.

The temperatures mentioned in the example are room temperatures unlessotherwise indicated. The temperatures, however, are not critical and thereactions may be carried out at higher or lower temperatures; butextremely high temperatures should be avoided because of the likelihoodof decomposition of the desired products which may result from operationat such temperatures.

Unless otherwise stated, the reagents can be used in differentproportions than are indicated in the above example as the proportionsunless otherwise indicated are not critical, although enough of thereagents should be employed to insure substantially complete reaction toproduce the desired products.

The specific rotation for A*--"-3,1l,20-triketo-l7(fl)-hydroxy-21-acetoxy'pregnene indicated by the symbol [a] wasdetermined in acetone solution using the D line of sodium.

Various changes and modifications might be made in my invention asdefined herein without departing from the scope thereof. It is myintention that these changes and modifications, to the extent that theyare comprehended within the scope of theappended claims, shall be considered as part of my invention.

What is claimed is:

l. The process that comprises partially esterifying A--3,l1-diketo-17,20,21-trihydroxypregnene by reaction with substantiallythe theoretical quantity of an acylating agent required to esterify onehydroxyl group, reacting the resultant ester with an oxidizing agent,and recovering a mixture containing A--"-3,ll.,20-triketo-1'7-hydroxy-21-acyloxypregnene and A--3,il,l'ltriketoandrostene.

2. The process that comprises partially esterifyingA--3,11-diketo-17,20,21-trihydroxypregnene by reaction withsubstantially the theoretical quantity of acetic anhydride required toesteriiy one hydroxyl group, reacting the resultant ester with chromiumtrioxide and recovering a mixture containing A"-3,11,20-triketo-17-hydroxy-zl-acyloxypresnene and A "-3,11,17- triketoandrostene. 3. Theprocess that comprises hydrolyzing A-3,11-diketo-17-hydroxy-20,2i-diacyloxypregnene to produceA"-3,11-diketo-1l',20,21-trihydroxypregnene, partially esteriiying thelastnamed compound by reaction with an acylating agent to produce A-'3,11-diketo-17,20-dlhydroxy-2l acyloxypregnene, and reacting thelatter substance with an oxidizing agent to form a mixture containing A-3,11,20-triketo-17-hydroxy-Zl-acyloxypregnene and A"-3,11,17-triketoandrostene.

4. The process that comprises hydrolyzing n-3,11-diketo-1'1-hydroxy-20,2i-diacyloxypre8- go nene to produce fl-3,11-diket0-1'7,20,21-trihydroxypregnene, partially esterifying thelastnamed compound by reaction with acetic anhydride to produce A-3,11-diketo-17,20-dihydroxy-21-acyloxypregnene, and reacting the lattersubstance with chromium trioxide to form a mixture containing A--3,11,20-triketo-17-hydroxy-ZI-acyloxypregnene and A -3,11,17-triketcandrostene.

LEWIS H. SARE'I'I.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,322,809 Logemann June 29, 19432,365,292 Ruzicka Dec. 19, 1944

